Glycopeptide and lipoglycopeptide antibiotics are a class of biologically produced or semi-synthetic antimicrobial agents with activity on bacterial cell walls and/or on membrane integrity (Williams, D. H et al, Angewandte Chemie International Edition in English (1999) 38: 1172-1193; Nicolaou, K. C. et al, Angewandte Chemie International Edition in English (1999) 38:2097-2152; Kahne, D. et al Chemical Reviews (2005) 105:425-448; Pace, J. L. et al, Biochemical Pharmacology (2006) 71:968-980). Well-known glycopeptide and lipoglycopeptide antibiotics include vancomycin, teicoplanin, oritavancin (U.S. Pat. No. 5,840,684), dalbavancin (U.S. Pat. No. 5,750,509) and telavancin (U.S. Pat. No. 6,635,618). The two first drugs have been proven clinically and microbiologically to have potent activity against gram-positive organisms and the latter three drugs are in clinical trials. Oritavancin, dalbavancin and telavancin possess extremely attractive pharmacological profiles with potent activity against gram-positive organisms, including methicillin-resistant Staphylococcus aureus, intermediate and fully vancomycin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus spp., and Streptococcus spp.
Glycopeptides are known to produce localized side effects upon administration and typically require large volumes for administration by infusion. The side effects present themselves as inflammatory responses such as phlebitis, pruritus and the “Red-Man” syndrome (Sivagnanam, S. et al, Critical Care (2003) 7:119-120; Bertolissi, M. et al, Critical Care (2002) 6:234-239; Wilson, A. P. R., International Journal of Antimicrobial Agents (1998) 10:143-152; Korman, T. M. et al, Journal of Antimicrobial Chemotherapy (1997) 39:371-381). The problem may be that the lack of solubility of the glycopeptide and/or its presence at high concentrations induces an inflammatory response. A prodrug which could simultaneously improve the solubility of the drug and mask its presence at the time and the site of administration may be able to decrease such inflammatory responses.
In addition, the lack of solubility of glycopeptide antibacterial agents results in the need for administration of low concentrations of the drug in large volumes over a prolonged period of time, which is an impediment in emergency situations where rapid administration is needed.
Improvements to the solubility of therapeutic materials in isotonic aqueous media can be brought about through a number of means (Stella V. J. et al Advanced Drug Delivery Reviews (2007) 59: 677-694). With respect to glycopeptides, improvements in solubility can be brought about by the use of poly(ethylene glycol) chains (WO2008118784), but at the cost of a marked increase in the size of the molecule administered.
In view of the above, there is a need for highly active glycopeptide antibiotics for the prevention and treatment of infections without the potential adverse events associated with their administration. More particularly, there is a need for glycopeptide and lipoglycopeptide antibiotics with the ability to overcome bacterial resistance, that can be administered in reduced volumes, and that have greater solubility in circulating biological fluids.
The present invention fulfills these needs and also other needs as will be apparent to those skilled in the art upon reading the following specification.